Cyclin-dependent kinases regulate lysosomal degradation of hypoxia-inducible factor 1α to promote cell-cycle progression.
Proc Natl Acad Sci U S A
; 111(32): E3325-34, 2014 Aug 12.
Article
em En
| MEDLINE
| ID: mdl-25071185
ABSTRACT
Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that mediates adaptive responses to oxygen deprivation. In addition, the HIF-1α subunit has a nontranscriptional role as a negative regulator of DNA replication through effects on minichromosome maintenance helicase loading and activation. However, some cell types continue to replicate under hypoxic conditions. The mechanism by which these cells maintain proliferation in the presence of elevated HIF-1α levels is unclear. Here we report that HIF-1α physically and functionally interacts with cyclin-dependent kinase 1 (Cdk1) and Cdk2. Cdk1 activity blocks lysosomal degradation of HIF-1α and increases HIF-1α protein stability and transcriptional activity. By contrast, Cdk2 activity promotes lysosomal degradation of HIF-1α at the G1/S phase transition. Blocking lysosomal degradation by genetic or pharmacological means leads to HIF-1α-dependent cell-cycle arrest, demonstrating that lysosomal degradation of HIF-1α is an essential step for the maintenance of cell-cycle progression under hypoxic conditions.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteína Quinase CDC2
/
Quinase 2 Dependente de Ciclina
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Subunidade alfa do Fator 1 Induzível por Hipóxia
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Pontos de Checagem do Ciclo Celular
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Lisossomos
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article